1. Field of the Invention
The present invention relates generally to image processing, and, more particularly, to systems and methods for processing medical image data to facilitate comparisons among groups of subjects.
2. Description of Related Art
United Nations military personnel returning from the 1991 Persian Gulf War reported post-war changes in mental function and physical performance that did not seem reasonably attributable to known maladies such as infectious diseases or post-traumatic stress disorder. A study by Haley et al. analyzed medical records, wartime exposures, responses from a survey instrument of illness symptoms, and psychological profiles of 249 U.S. Naval reservists of the 24th Reserve Naval Mobile Construction Battalion (“seabees”) who were stationed in the Gulf War theater of operations.
They characterized three primary medical syndromes that were shared by approximately one-third of the 175 seabees who complained of serious health problems believed to have resulted from service in the Gulf War. Kang et al. confirmed the syndromes in a stratified sample of all the military personnel who were deployed in the war. In a clinical study of 26 affected Gulf War veterans and 20 matched controls, Haley et al. (1997b) concluded that the observed abnormalities in brain functioning were consistent with subcortical and brainstem dysfunction. In an epidemiological study of self-reported risk factors of the 249 seabees, Haley et al. found that the three primary syndromes were consistent with chemical exposures but not with other proposed risk factors such as oil well fires or combat stress. Postulating that the syndromes were due to deep-brain irregularities or malfunctions, a subsequent study of 39 syndrome and control seabees using single-photon emission computed tomography (SPECT) brain imaging was undertaken.
Impaired cognition (“Syndrome I”) was characterized by distractibility, difficulty remembering, depression, insomnia, confused thought processes, and migraine headaches. Confusion ataxia (“Syndrome II”) was characterized by difficulty with thinking and reasoning, confusion with where one is or what one is doing, disorientation, balance problems, sensations of rooms spinning, stumbling, physician diagnosis of post-traumatic stress disorder, liver disease, or sexual impotence. Central pain (“Syndrome III”) was characterized by joint and muscle pain, muscle fatigue, tingling, and numbness. Haley et al. attributed these syndromes to neurological damage, possibly from exposure to chemical nerve agents, anti-nerve gas medication, pesticides, or high concentrations of insect repellants in genetically predisposed individuals. They postulated that exposure to these agents might have caused damage in the basal ganglia or the brainstem, which are gray-matter structures deep within the brain.
In an attempt to identify areas of the deep brain that might have been affected by exposures in the Gulf War, an experiment was conducted with the voluntary participation of five “Syndrome I subjects,” twelve “Syndrome II subjects,” five “Syndrome III subjects,” and seventeen “control subjects” from the original study of 249 seabees. The small numbers of subjects in each group reflect the costs (medical personnel, housing, medications, and tomography) incurred in performing multiple brain scans on each of these subjects by Haley et al. (The larger relative number of subjects in the Syndrome II group is due to previous neurological studies that indicated this group was the most severely affected.)
In that study, control subjects were closely matched by age, gender, and education to the Syndrome II subjects. Nine of the controls served in the Gulf War theater of operations but did not subsequently report any adverse health effects. Eight of the controls remained in the United States. Since no substantive differences were detected between the two groups of control subjects, they were combined for the analysis reported below.
Between December of 1997 and June of 1998, SPECT scans of brain activity were obtained on each subject during a baseline session and 2-5 days later in a treatment session. The goal of the SPECT imaging was to determine the extent of brain activity through measurements of the rate of cerebral blood flow. A radioactive tracer was introduced into each subject's blood through a rapid intravenous injection. Differential blood flow in the brain causes more radiation to be emitted in active brain areas where the rate of blood flow is relatively high and less to be emitted in areas where blood flow is reduced by inactivity, normal inhibition, or impairment. In the baseline session, the patients were administered the radioactive tracer after an intravenous infusion of a placebo, saline. In the treatment session, physostigmine was added to the saline infusion. Physostigmine elevates acetylcholine, which typically inhibits brain activity in normally functioning gray-matter regions of the brain. It was anticipated that healthy brain regions for both syndrome and control groups would exhibit inhibited gray-matter brain activity in the treatment session. While it was suspected that dysfunctional gray-matter brain regions in the syndrome subjects that were damaged by Gulf War exposures would show little or no change between the baseline and treatment sessions, there was no conclusive information from previous clinical investigations about the nature of the effects of physostigmine on dysfunctional brain regions.
As a result, SPECT intensity counts were then made available for approximately 200,000 2×2×2 mm3 volume elements, or voxels, of each of the 39 subject brains at each measurement session. Nonetheless, conventional methods of brain image analysis at individual brain locations have been unable to detect any significant differences in brain activity among these various groups. The size and complexity of brain imaging databases confront statistical analysts with a variety of issues when assessing brain activation differences between groups of subjects. Detecting small group differences in activation is compounded by the need to analyze hundreds of thousands of spatially correlated measurements per image. These analyses are especially problematic when, as is typical, the number of subjects in each group is small.
In light of the foregoing, the inventors hereof have recognized a need for new systems and methods for processing medical image data with increased sensitivity to facilitate comparisons among groups of subjects.